ISSN 0975-2366

DOI:https://doi.org/10.31838/ijpr/2021.13.02.056
Research Article

Molecular Docking Study for Covid-19 of Curcumin

and Tetrahydrocurcumin Analog
RITMALENI*1, HARI PURNOMO1, RAIHAN AJI PANGESTU3 AND MAYWAN HARIONO2
1
Laboratory of Medicinal Chemistry, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta,
Indonesia.
2
Faculty of Pharmacy, Sanata Dharma University, Kampus III, Paingan, Maguwoharjo, Depok, Sleman,
Yogyakarta, Indonesia.
3
Curcumin Research Center, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia.
*Corresponding Author
Email ID: ritmaleni@ugm.ac.id
Received: 23.11.20, Revised: 15.12.20, Accepted: 17.01.21

ABSTRACT
Analogs of curcumin and tetrahydrocurcumin are compounds that have been studied for a long time for their
biological activities such as anticancer, antibacterial, antioxidant, antidiabetes and antiviral. This research is
aimed to study the potency of curucmin and tetrahydrocurcumin analogs as antiviral agent against papain-like
protease/deubiquitinase protein in Covid-19 drug virtually by using molecular docking of the analogs against
3E9S protein with PLANTS and MOE used as the docking programs. The results show that THHGV-6 is the
most promising compound by using MOE method while THA-104 is the most potent one by using plants
method. THA-102 is the most potent compound among all the tested ligands by using both MOE and PLANTS
method. None of curcumin analogs show antiviral potency but many analogs of tetrahydrocurcumin show
antiviral potency against 3E9S. This is in which may be developed further as antiSARS-Covid.
Keywords : curcumin analog, Covid-19, molecular docking, tetrahydrocurcumin

INTRODUCTION virus.[12] This drug is recommended for

Corona Virus Disease in year of 2019 (Covid-
19) is a pandemic of infectious disease that is
most watched out this day. Medicine or vaccine
to combat this disease for therapy and
prevention are not available yet around the
world. Researchers are racing with time to get
the medicine or vaccine. One of the efforts that
can be done possibly and urgently is
repositioning the commercial available drugs.
Researchers around the world have reported
about those possibilities of using the
commercial available drugs for treatment of
Covid-19 in many scientific journals. The
researches were done by doing a virtual
screening, a molecular docking method[1-6] to
some molecules[7-8].
In June 2020, some anti-infective drugs like
favipiravir, remdesivir and lopinavir have been
used at last step test on human phase III and IV
clinic tests. This test is carrying out
internationally. Lopinavir is used to use as anti-
human immunodeficiency virus (HIV). Some
researchers reports that lopinavir is effective
against SARS-CoV.[9-11] Favipiravir is a new
agent for inhibitor RNA-dependent RNA
polymerase (RdRp). It is normally used as
antiinfluenza, Faviravir also inhibit the
replication processes of flavi-, alpha-, filo-,
bunya-, arena-, noro-, and other RNA in a
treatment of SARS-CoV-2 on 14 Februari
2020.[9,13] While Remdesivir is an analog of
nucleoside which can inhibit the infection of SARS-
CoV-2.[14]
Curcumin and curcumin analogs have been
reported to have an antiviral activity. [15-20]
As curcumin has been proposed as a new
treatment option against Covid-19. [21-24]
Comparative Docking Studies on Curcumin
with COVID-19 Proteins has also been
performed by some researches recently.[25] In
this present study the screening of the activity
of curcumin analog activity as antiCovid-19
were carried out. The analog of curcumin that
used in this study is the substituted-
benzylidene/benzyl-cyclohexanone. MOE and
PLANTS software are used for this study. Protein
3E9S is as the receptor. 3E9S is a new class of
papain-like protease/deubiquitinase inhibitors
blocks SARS virus replication. This research is
aimed to repurposing the use of curcumin
analogs compound as antiCovid-19 agent. In
order to see the possibility of their potency, two
docking programs were used.
MATERIALS AND METHODS
PDB 3E9S (rscb.org) is the protein that used for
the screening virtually of analog of curcumin and
tetrahydrocurcumin in studying its activity as

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 Ritmaleni et al / Molecular Docking Study for Covid-19 of Curcumin and Tetrahydrocurcumin Analog

antiviral, antiSARS-Covid. This protein is a which analysed by dB COMBINE calculation.

complex of hydrolase protein and its inhibitor. By
inhibiting this hydrolase, it could halt the
replication process of a virus. The reference
ligand is code as TTT. Docking based QSAR
method is used in this study. It aims to increase
the accuracy and validity of tests because
sometimes S value gives an error in study as false
positive/negative. Two descriptors are used in this
study, intermolecular and interaction descriptors
Base data that need in this screening are tested
ligands, reference ligand, protein complex and
native ligand in order to generate a QSAR
equation. This equation can be used to predict
IC50 value of tested compounds. PLANTS is free
software for molecular docking while MOE is a
license software to Faculty of Pharmacy, Gadjah
Mada University.

Table 1: List of tested ligands

Code R1 O R1 R1 O R1
R2 R2 R2 R2
or
R3 R5 R5 R3 R3 R5 R5 R3
R4 R4 R4 THA series R4
A series
-R1 -R2 -R3 -R4 -R5
A-102/THA-102 OH Oet H H H
A-103/THA-103 H Oet OH H H
A-104/THA-104 H NO2 H H H
A-108/THA-108 H COH H H H
A-111/THA-111 OMe H H Ome H
A-113/THA-113 H Br OH Br H
A-129/THA-129 OMe H H H H
A-146/THA-146 H OH H H H
HGV-5/THHGV-5 H Ome OH Ome H
HGV-6/THHGV-6 H Cl OH Cl H

The Native ligand in this screening is taken from CHEMBL data which has TTT code and also has an IC
value as antiviral.

RESULT AND DISCUSSION
A. Docking by using MOE
1. Prediction of pose validation
Before docking the tested compound, the native
ligand is redocked in order to get the RMSD value
below 2. This result determines the validity of
used docking method. The native ligand, TTT,
showed the RMSD < 2 as seen on picture below.
Fig.1: Pose of TTT ligand
It can be seen that TTT compound and reference
ligand are in a similar pose. This docking method
is done by using pocket as site and alpha triangle
as placement method.
2. QSAR equation generation
QSAR equation generation is carried out
according to these steps: docking, pose choice,
descriptor calculation, QSAR equation generation
and QSAR equation validity. The validity of QSAR
equation is based on the correlation between
experimental data and prediction data, where the
correlation has to have the correlation value
above 0.9.
Native ligand is taken from CHEMBL with its IC50
value. Next step is docking process to determine
the value of descriptor interaction and continued
by choosing the most rational pose in one
receptor. Then the calculation of intermolecular
descriptor and descriptor interaction are carried.
After that the QSAR equation is generated with
equation like below:
IC50= -56983.9 + -3391.05 * GLY_267_E + -
58950.9 * Largest_Neg_Hardness + -3779.93 *
PC- + 73169.1 * PEOE_RPC- + -3741.58 *
PM3_HOMO + 3959.6 * PM3_LUMO +
2520.36 * SER_246_V + 43738.9 *

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 Ritmaleni et al / Molecular Docking Study for Covid-19 of Curcumin and Tetrahydrocurcumin Analog

Smallest_Rs_mol_i + -12145 * THR_302_E + 3. Docking based QSAR of tested ligands

656.963 * TYR_269_E + 885.049 * andrews + -
25009.1 * lip_violation + 749.437 * vsurf_DW12
+ 1647.28 * vsurf_ID8 + -3974.46 * vsurf_IW1.
This equation is used to predict the IC50 value of
tested ligands.
Docking based QSAR of tested ligands can
predict the IC50 values of tested ligands. The
results are like below:

Table 2: Prediction of IC50 of tested ligands

No Code IC50 S No Code IC50 S
prediction MOE prediction MOE
1 A-102 7583.9141 -4.0803 11 THA-102 12807.2393 -4.8523
2 A-103 7214.8584 -5.1302 12 THA-103 37008.2695 -5.6789
3 A-104 41287.0664 -5.9893 13 THA-104 52541.6992 -6.1114
4 A-108 16534.7969 -5.3334 14 THA-108 18987.3848 -5.5584
5 A-111 29951.9004 -4.7596 15 THA-111 10186.7109 -4.2120
6 A-113 27677.3984 -4.2071 16 THA-113 10917.1416 -5.9859
7 A-129 35751.8672 -4.7240 17 THA-129 39385.8359 -5.5801
8 A-146 41787.3281 -4.1506 18 THA-146 49150.5352 -5.9581
9 HGV-5 32413.1895 -48458 19 THHGV-5 43782.0664 -5.3765
10 HGV-6 1961.4438 -5.9752 20 THHGV-6 11353.9346 -5.8028
TTT 29646.2148 -5.9024 TTT 29660.0098 -5.9022

From the table above, it is found that HGV-6 has as antiviral. Its pose and interaction should be
the best IC50 among tested ligands. But it does checked as shown in figure 3 below.
not mean that this compound is the potential one

Fig.3: Pose and interaction of HGV-6

Some compounds have IC50 value better than
reference ligand, TTT. But when the interaction
between ligand and receptor (pose) is looked
closely, the pose of HGV-6 is far from reference
ligand. This results a false positive activity. While
two other compounds, THHGV-6 and THA-102
(Figure 4 and 5), have similar poses with
reference ligand when they interacted with
receptor. These two ligands also interacted with
amino acid residues as the same way with
reference ligand’s interaction. Analog curcumins
seem that have rigid structures which make them
difficult to interact with receptor. This is according
to the double bonds on their structures. This
condition is not found on the analog of
tetrahydrocurcumin structures. It seems that
analog of tetrahydrocurcumins has better
potential as antiviral agents.

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Fig.4: Pose and residue interaction of THHGV-6

Fig.5: Pose and residue interaction of THA-102

B. Docking by using PLANTS as protein viewer. After redocking is completed, it

Docking process by using PLANTS is similar with
by using MOE. Ligand preparation, protein
preparation, docking and data analysis are the
works that done with PLANTS. But in PLANTS
method, no QSAR equation is built and need
some viewer for preparation processes. Marvin
sketch is used for ligand preparation, Yasara for
protein preparation, plants for docking and excel
for data analysis. These are the advantages of
using PLANTS. Not user friendly is the
disadvantage of this docking by PLANTS and also
its data transfer is difficult sometimes.
The validation process of docking is determined
by RMSD value of redocking of reference ligand.
PLANTS calculate the score directly to figure out
the affinity. RMSD value is calculated on Yasara
is found that its RMSD value is 0.5 like figure
below. This informed that the docking method is
valid to predict the pose between ligand and
receptor. Docking process of 20 tested
compounds was carried after the validation steps.
Each ligand are prepared one by one by
protonation step and searched for best
conformations. Data then are saved in each
tested ligand’s folder. After docking processes are
finished, it was found that THA-104 has a better
score compared to reference ligand’s score and
has a similar pose with TTT’s pose as viewed by
Yasara viewer.
The results of molecular docking study of
curcumin and tetrahydrocurcumin analogs by
using PLANTS program is tabled like below.

Table 3: S value of tested ligands by using PLANTS

No Code S PLANTS No Code S PLANTS
1 A-102 -78.171 11 THA-102 -107.182
2 A-103 -84.725 12 THA-103 -101.860
3 A-104 -84.725 13 THA-104 -103.515
4 A-108 -84.168 14 THA-108 -102.575
5 A-111 -77.354 15 THA-111 -100.520

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6 A-113 -84.831
7 A-129 -81.226
8 A-146 -85.431
9 HGV-5 -79.913
10 HGV-6 -84.829
TTT -110.634
The comparisons of interaction between THA-102
and TTT with their corresponding amino acids are
visualized by using ligPlus program like figure 7
below. The Amino acids that are responsible to
interact with THA-102 are Val117,Leu151,
Ile152,Met170, and Leu173. While Amino acids
Leu121 and Phe148 do not have interaction with
Fig.6: The interaction between THA-102 and TTT with their corresponding amino acids
According to pair t test analysis of all ligands, it is
observed that all tested compounds are not
potential enough as antiviral agent. But THA-104
has a close result to reference ligand by using
PLANTS for its docking data. From all above
docking processes, analog tetarhydrocurcumin
have better scores compared to curcumin
analogs’ scores. This is because probably
according to structure flexibilities that makes them
easier in adaption with receptor.
C. The comparison between docking results
from PLANTS and MOE
According to MOE docking result, compounds
that have good potential as antiviral are THA-104
and THA-146 while according to PLANTS docking
result, compound that has good potential as
antiviral is THA-102. THA-146 (score = -5.958)
has a better scoring function value compared to
TTT (score = -5.902) on MOE. THA-102 (score =
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16 THA-113 -96.650
17 THA-129 -96.835
18 THA-146 -103.723
19 THHGV-5 -97.093
20 THHGV-6 -96.410
TTT -110.634
THA-102. The Amino acids that have interaction
with TTT are Val117, Leu121, Phe148, Leu151,
Ile152,Met170,and Leu173. While there are two
amino acids, Leu121 and Phe148 that do not
interact with THA-102 but interact with TTT.
-107.182) is less stable compared to TTT (score =
-110.634) on PLANTS. This result shows that in
silico THA-104 is a potential compound against
Severe acute respiratory syndrome-related
coronavirus (SARS-related corona virus) on MOE.
THA-104 has the best scoring function result on
MOE among the tested ligands but has a low
result on PLANTS. This result is probably because
of the different way of score calculation and its
placements on both. THA=146 still has a good
score compared to other curcumin analogs. On
other side, THA-102 has the best scoring function
on PLANTS but not on MOE. This is again
because of the different on the placement of the
ligands and scoring function calculation. If based
on S value on MOE, THA-104 has the best value
among all the tested ligands.
CONCLUSION
 Ritmaleni et al / Molecular Docking Study for Covid-19 of Curcumin and Tetrahydrocurcumin Analog

THHGV-6 is the most possible potential 8. Shivanika, C., Kumar, D. S., Ragunathan, V.,
compound by using MOE program while THA- Tiwari, P., Sumitha, A., & Devi, P. B. (2020).
104 is the most possible potential one by using Molecular docking, validation, dynamics
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potential compound among all the tested ligands natural compounds against the SARS-CoV-2
by using both MOE and PLANTS programs. main-protease. Journal of Biomolecular Structure
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AKNOWLEDGEMENT
Z., Liu, A., Shao, Y., Hua, W., Zhang, T., Wu, H.,
Thanks to Kemenristek-BRIN for funding (No :
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2948/UN1.DITLIT/DIT-LIT/PT/2020) tolerability of lopinavir/ritonavir- and efavirenz-
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